Value of sonoelastography for diagnosis of breast non-mass lesions and comparison with BI-RADS: A systematic review and meta-analysis

Background: Not all the breast lesions were mass-like, some were non-mass-like at ultrasonography. In these lesions, conventional ultrasonography had a high sensitivity but a low specificity. Sonoelastography can evaluate tissue stiffness to differentiate malignant masses from benign ones. Then what about the non-mass lesions? The aim of this study was to evaluate the current accuracy of sonoelastography in the breast non-mass lesions and compare the results with those of the American College of Radiology breast Imaging-Reporting and Data System (BI-RADS). Methods: An independent literature search of English medical databases, including PubMed, Web of Science, Embase & MEDLINE (Embase.com) and Cochrane Library, was performed by 2 researchers. The accuracy of sonoelastography was calculated and compared with those of BI-RADS. Results: Fourteen relevant studies including 1058 breast non-mass lesions were included. Sonoelastography showed a pooled sensitivity of 0.74 (95% CI: 0.70–0.78), specificity of 0.89 (95% CI: 0.85–0.91), diagnostic odds ratio (DOR) of 25.22 (95% CI: 17.71–35.92), and an area under the curve of 0.9042. Eight articles included both sonoelastography and BI-RADS. The pooled sensitivity, specificity, DOR and AUC were 0.69 versus 0.91 (P < .01), 0.90 versus 0.68 (P < .01), 19.65 versus 29.34 (P > .05), and 0.8685 versus 0.9327 (P > .05), respectively. Conclusions: Sonoelastography has a higher specificity and a lower sensitivity for differential diagnosis between malignant and benign breast non-mass lesions compared with BI-RADS, although there were no differences in AUC between them.


Introduction
According to the American College of radiology breast imaging-reporting and data system (BI-RADS) lexicon for breast ultrasound (US), a mass is defined as a space-occupying lesion seen in 2 different planes and can be distinguished from normal anatomic structures. [1]However, not all breast lesions strictly meet the criteria described by BI-RADS, such as tubular hypoechoic duct-like structures, ill-defined geographic hypoechoic lesions, or architectural distortion. [2,3]Symptoms of these non-mass lesions include palpable breast mass, breast pain, nipple discharge, etc.These clinical manifestations lack specificity, making them susceptible to being misdiagnosed or missing a diagnosis.It has been reported that conventional US has a high sensitivity of 95.35% but a low specificity of 43.24% in the diagnosis of non-mass lesions. [3]5][6][7] For patients with suspected breast lesions, biopsy is usually recommended to confirm the diagnosis, but studies have shown that the histological consistency between US-guided coreneedle biopsy (US-CNB) and surgical histological diagnosis was significantly better in mass lesions than in non-mass lesions. [3]oreover, according to reports, 53.8% to 72.7% of breast non-mass lesions were benign, [8,9] and excessive reliance on biopsy may increase the psychological and economic burden on these patients.Therefore, more technology is required to offer valuable information for the identification of breast non-mass lesions, aiding doctors in developing appropriate treatment regimens.
Sonoelastography is an innovative US technique that evaluates tissue stiffness based on the principle that malignant tissues are generally harder than benign tissues. [6][12] However, few research has focused on breast non-mass lesions.Some studies have shown that sonoelastography has important value in the diagnosis of breast diseases, especially for non-mass lesions. [13,14]The aim of our study was to summarize the diagnostic performance of sonoelastography for breast non-mass lesions and determine the application value of this technology.

Materials and methods
All analyses were based on previously published studies; thus, no ethical approval or patient consent were required.

Literature search
Two independent researchers performed the study in accordance with the PRISMA recommendations. [15,16]The PubMed, Web of Science, Embase & MEDLINE (Embase.com), and Cochrane Library databases were searched to identify all studies that assessed differential diagnosis between malignant and benign breast non-mass lesions.Table 1 shows the search strategy.Duplicate articles were manually excluded.Unpublished relevant data were also considered, but no suitable studies were appropriate for inclusion.The literature search was updated until March 23, 2024.

Inclusion and exclusion criteria
Two researchers assessed the articles independently.The inclusion criteria were as follows: the study was approved by an ethics committee or institutional review board; sonoelastography was performed for the breast non-mass lesions in the study; surgery, US-CNB, and/or US-guided vacuum-assisted biopsy (US-VAB) results were used as the reference standard in the study; reported data were necessary to identify the true positive (TP), false positive (FP), false negative (FN), and true negative (TN) cases.The exclusion criteria were as follows: case reports, letters, reviews, editorial comments, conference reports, and articles that were not published in English; in the presence of insufficient data, the corresponding authors were contacted via email to request missing data, but there was no response within 15 days; in cases where 2 or more studies were performed by the same department in an overlapping period, studies with a smaller number of patient samples were excluded.All the disagreements were resolved by consensus.

Data extraction
The data were extracted by 2 investigators independently.All relevant data from the included studies were extracted, including first author, country where the study was performed, publication year, patient age, symptoms, number of patients, number of lesions, lesion size, reference standard, type of lesions, US system that was used in the study, index of elastography, cutoff value, and number of TPs, FPs, FNs, and TNs.In articles including BI-RADS, the TPs, FPs, FNs, and TNs of BI-RADS were also acquired.The Youden method was used to define the cutoff value if the value was not clearly provided by the author.All the disagreements were resolved by consensus.

Quality assessment
Methodological quality was assessed using the quality assessment of diagnostic accuracy studies criteria. [17]The defined questions were answered as yes, no, or unclear and were assigned 1 point, 0 point, and 0.5 point, respectively.All the items in the questions were completed by 2 researchers independently.Disagreements were resolved by consensus.

Data analysis
The statistical software STATA (Version 18.0, Stata Corporation), Meta-Disc (Version 1.4, Unit of Clinical
Table 2 shows the main characteristics of the included studies.
In one study with insufficient data, the missing data were provided by the corresponding author via email. [22]There were 2 studies from the same department: one was performed between April 2013 and February 2016 and included 85 breast non-mass lesions, [19] and the other was performed from December 2014 to November 2016 and included 82 lesions. [29]Thus, the latter article was excluded.Excellent interobserver agreement was observed when the studies were excluded by title and abstract (κ = 0.881).In other steps, there was no disagreement between the 2 observers (κ = 1).

Quality assessment
Table 3 shows the quality assessment of each study.All the included studies scored at least 13 points, indicating that they were "high" quality studies.However, in 13 of the 14 included studies, it was unclear whether pathologists were blinded to the sonoelastography results.In 2 studies, it was unclear if readers of sonoelastography were blinded to the histological results.The interobserver agreement was excellent between the 2 researchers (κ = 0.816).

Comparison between sonoelastography and breast imaging-reporting and data system
There were 8 articles including both sonoelastography and BI-RADS.The cutoff value of BI-RADS was set at 4A because the highest Youden index was obtained when the value was over it in most of the articles.The pooled sensitivity, specificity, DOR and AUC were 0.69 versus 0.91 (P < .01),0.90 versus 0.68 (P < .05),19.65 versus 29.34 (P > .05),and 0.8685 versus    Ko KH et al [7]   Choi JS et al [18] Li L et al [19] Park SY et al [20] Wang, ZL et al [21] Graziano L et al [22] Qu, XX et al [23] Xu, P et al [25] Sefidbakht S et al [24] Guo, WJ et al [26] Li, JN et al [13] Wang, FX et al [27] Kayadibi, Y et al [28] 1: Was the spectrum of patient representative of the patients who will receive the test in practice?0.9327 (P > .05) in sonoelastography and BI-RADS, respectively (Fig. 3).

Heterogeneity assessment
Statistical analysis revealed no heterogeneity arising from the threshold effect (Spearman correlation coefficient: 0.455, P = .102).The Cochran Q test and the I 2 test of DOR revealed no other heterogeneity with P = .295and I 2 = 14.5%.

Publication bias
Deek's funnel plot was used to explore publication bias, which showed no significant differences in this meta-analysis (P = .716)(Fig. 4).

Discussion
Conventional US is widely used to identify or diagnose breast diseases.However, the differentiation of breast non-mass lesions by ultrasonography is still unclear, and there is significant overlap between the image features of malignant and benign lesions. [26]Sonoelastography is an innovative ultrasonographic technique for assessing tissue stiffness.[12] Among the possible debates surrounding sonoelastography, it should be included whether the method can be applied to non-mass lesions.Some authors described that there were no statistically significant differences in the diagnostic performance of sonoelastography between mass and non-mass lesions. [6]Nevertheless, others described that the exclusion of non-mass lesions could improve their sensitivity and specificity values compared to other series and considered that interspersed healthy tissue could possibly lead to FN results. [30]ur current meta-analysis showed a pooled sensitivity of 74% and a pooled specificity of 89% for differentiating between malignant and benign breast non-mass lesions.The specificity was similar to that of mass lesions, which was approximately 84.8% to 90.2%.However, the sensitivity seemed lower than that of mass lesions, which was approximately 85.5% to 88.8%. [10- 12]Similar results were found when compared with BI-RADS.Sonoelastography had a higher pooled specificity (0.90 vs 0.68) but a lower sensitivity (0.69 vs 0.91) than BI-RADS, although there were no differences in AUC (0.8685 vs 0.9327) between them.One reason for the lower sensitivity was probably due to the high percentage of in situ lesions in the non-mass lesions.For example, there were 195 lesions of DCIS from the 491 malignant lesions in the 13 studies that provided detailed pathological results, occupying 39.71%.It was indicated that DCIS showed a significantly lower stiffness value than invasive ductal cancer in the literature. [7]Another reason for the lower sensitivity may be the size.The mean diameters were no more than 30 mm in most of the studies.A smaller lesion size was associated with FN shear wave elastography results for malignant non-mass lesions in the literature. [20]Interestingly, the size of the lesions included in Wang ZL et al's study was the largest among these studies (mean diameter, 41.4 mm), but the sensitivity of sonoelastography in this study was only 0.58, significantly lower than the pooled sensitivity. [21]This may be related to differences in histopathology and may indicate that sonoelastography is particularly suitable for breast non-mass lesions of a certain size range, rather than larger lesions being more easily diagnosed by this technique.The relationship between lesion size and sonoelastography performance still needs further research.
In recent years, more and more researchers have noticed the diagnostic value of elastography for breast non-mass lesions.Guo W et al established a predictive model for identifying the properties of breast non-mass lesions using conventional US, strain elastography (SE), and contrastenhanced ultrasound (CEUS).Its sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated to be 98.0%, 94.0%, 94.3%, 97.9%, and 96.0%, respectively. [26]Li S-Y et al analyzed the features of breast non-mass lesions on B-mode US, CEUS, and shearwave elastography (SWE) and discovered that the combination of conventional US and SWE had the highest AUC of 0.935. [14]Wang F et al explored the combined application of SWE and a novel blood flow imaging technique called Angio PLUS microvascular US imaging for diagnosing breast nonmass lesions and found an accuracy of 78.3% to 88.3%. [27]hese studies indicated that sonoelastography played a good complementary role on conventional US.
A similar meta-analysis about sonoelastography for breast non-mass lesions was reported in 2021. [31]In comparison to the 2021 meta-analysis, our study had the following differences: First, the literature included in our study was different.Two articles were excluded: one because the main text was written in Italian, [32] and the other because 2 studies were conducted in the same department, [19,29] which may have some duplicate data, and the article with fewer lesions was excluded.Meanwhile, 5 new publications were included, with the corresponding author of one article providing the requisite data by email, [22] while the other four were new studies in recent years.Second, given the widespread application of BI-RADS in clinical practice, we explored the differences between BI-RADS and sonoelastography, and the findings revealed that the latter had significantly higher specificity, which can be helpful to reduce misdiagnosis.Third, in the 2021 meta-analysis, meta-regression and subgroup analyses suggested that measurement indexes (quantitative or qualitative), the country of origin (China or others), and the number of lesions were possible sources of heterogeneity. [31]owever, statistical analysis indicated no heterogeneity arising from the threshold effect in our study.The Cochran Q test and the I 2 test of DOR revealed no other heterogeneities.To be prudent, meta-regression was also performed in the above indexes in our study, but there were still no heterogeneities revealed, which may be for the different included articles between us.
There are some limitations in our study.First, few studies were included (i.e., fourteen).Second, unpublished data failed to be acquired, and language limitations might have affected the reliability of the results.Third, we did not analyze some factors that may influence image quality and overall diagnostic accuracy, such as pathological changes (e.g., calcification), race, breast thickness, lesion depth, and readers.Fourth, the value of sonoelastography combined with BI-RADS should be evaluated.However, that was only performed in 4 articles which showed a sensitivity of 0.61 to 0.97 and a specificity of 0.55 to 0.97. [6,13,18,21]Therefore, it was not performed due to the few studies.Finally, this study was not registered, and there may be a risk of human bias.

Conclusions
In conclusion, this meta-analysis shows that sonoelastography has a higher specificity and a lower sensitivity for differential diagnosis between malignant and benign breast non-mass lesions compared with BI-RADS, although there were no differences in AUC between them.Effective application of sonoelastography can prevent the misdiagnosis of patients with benign lesions and avoid unnecessary medical treatment.More efforts should be made to combine these 2 methods and other technologies to evaluate if better accuracy can be achieved in the future.

Figure 1 .
Figure 1.The research selection and literature retrieval process of this paper (a total of 10 studies).

3 : 4 : 5 : 6 : 7 : 8 : 9 : 10 : 11 : 12 :
Is the reference standard likely to correctly classify the target condition?Is the time period between reference standard and index test short enough to be sure that the target condition did not change between the 2 tests?Did the whole sample, or a random selection of the sample, receive verification using a reference standard of diagnosis?Did patients receive the same reference standard regardless of the index test result?Was the reference standard independent of the index test (i.e., the index test did not form part of the reference standard?).Was the execution of the index test described in sufficient detail to permit replication of the test?Was the execution of the reference standard described in sufficient detail to permit replication?Were the index test results interpreted without knowledge of the results of the reference standard?Were the reference standard results interpreted without knowledge of the results of the index test?Were the same clinical data available when test results were interpreted as would be available when the test is used in practice?Li et al. • Medicine (2024) Medicine

Figure 2 .
Figure 2. The Forest map results of sensitivity (A), specificity (B) and DOR (C) of sonoelastography for diagnosis and SROC curve of sonoelastography diagnostic accuracy obtained in this paper (D).DOR.DOR= diagnostic odds ratio, SROC = receiver operating characteristic.

Figure 3 .
Figure 3.The Forest map results of sensitivity (A, B) and specificity (C, D) of sonoelastography and BI-RADS for diagnosis, respectively and summary receiver operating characteristic (SROC) curve of their diagnostic accuracy obtained in this paper (E, F).BI-RADS = breast imaging-reporting and data system, SROC = summary receiver operating characteristic.

Table 1
Search strategy of each database.

Table 2
Main characteristics of included studies.